Physiology and Pathology of Infectious Diseases: The Autoimmune Hypothesis of Chagas Disease

Infectious pathologies are a group of diseases that contribute with great impact on public health worldwide. Among the various diseases, some have a higher epidemiological importance, since their morbidity and mortality are very significant. In addition to the usual immune response, mounted against noxious agents, there is still the concept of infection-induced autoimmunity. Autoimmune diseases are defined as illnesses in which the evolution from benign to pathogenic autoimmunity takes place. However, proving a disease to be of autoimmune etiology is not a simple task. It is well known that both genetic influences and environmental factors trigger autoimmune disorders. However, some theories are still under great discussion. One of the most intriguing self-induced disorders is the hypothesis of autoimmunity during Chagas disease. Since the mid-1970s, the Chagas autoimmunity hypothesis has been considered an important contributor to the complex immune response developed by the host and triggered by Trypanosoma cruzi. New ideas and findings have strengthened this hypothesis, which has been reported in a series of publications from different groups around the world. The aim of this chapter is to discuss the mechanisms involving autoimmunity development during Chagas disease

Surveillance of SARS-CoV-2 immunogenicity: loss of immunodominant HLA-A*02-restricted epitopes that activate CD8+ T cells

Introduction and methodsIn this present work, coronavirus subfamilies and SARS-CoV-2 Variants of Concern (VOCs) were investigated for the presence of MHC-I immunodominant viral peptides using in silico and in vitro tools.ResultsIn our results, HLA-A*02 haplotype showed the highest number of immunodominant epitopes but with the lowest combined prediction score. Furthermore, a decrease in combined prediction score was observed for HLA-A*02-restricted epitopes when the original strain was compared to the VOCs, indicating that the mutations on the VOCs are promoting escape from HLA-A2-mediated antigen presentation, which characterizes a immune evasion process. Additionally, epitope signature analysis revealed major immunogenic peptide loss for structural (S) and non-structural (ORF8) proteins of VOCs in comparison to the Wuhan sequence.DiscussionThese results may indicate that the antiviral CD8+ T-cell responses generated by original strains could not be sufficient for clearance of variants in either newly or reinfection with SARS-CoV-2. In contrast, N epitopes remain the most conserved and reactive peptides across SARS-CoV-2 VOCs. Overall, our data could contribute to the rational design and development of new vaccinal platforms to induce a broad cellular CD8+ T cell antiviral response, aiming at controlling viral transmission of future SARS-CoV-2 variants

Analysis of the immunological biomarker profile during acute zika virus infection reveals the overexpression of CXCL10, a chemokine linked to neuronal damage

BACKGROUND Infection with Zika virus (ZIKV) manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications and little is known about Zika immunopathogenesis. OBJECTIVES To define the immunologic biomarkers that correlate with acute ZIKV infection. METHODS We characterized the levels of circulating cytokines, chemokines, and growth factors in 54 infected patients of both genders at five different time points after symptom onset using microbeads multiplex immunoassay; comparison to 100 age-matched controls was performed for statistical analysis and data mining. FINDINGS ZIKV-infected patients present a striking systemic inflammatory response with high levels of pro-inflammatory mediators. Despite the strong inflammatory pattern, IL-1Ra and IL-4 are also induced during the acute infection. Interestingly, the inflammatory cytokines IL-1β, IL-13, IL-17, TNF-α, and IFN-γ; chemokines CXCL8, CCL2, CCL5; and the growth factor G-CSF, displayed a bimodal distribution accompanying viremia. While this is the first manuscript to document bimodal distributions of viremia in ZIKV infection, this has been documented in other viral infections, with a primary viremia peak during mild systemic disease and a secondary peak associated with distribution of the virus to organs and tissues. MAIN CONCLUSIONS Biomarker network analysis demonstrated distinct dynamics in concurrence with the bimodal viremia profiles at different time points during ZIKV infection. Such a robust cytokine and chemokine response has been associated with blood-brain barrier permeability and neuroinvasiveness in other flaviviral infections. High-dimensional data analysis further identified CXCL10, a chemokine involved in foetal neuron apoptosis and Guillain-Barré syndrome, as the most promising biomarker of acute ZIKV infection for potential clinical application. © 2018, Fundacao Oswaldo Cruz. All rights reserved

Panoramic snapshot of serum soluble mediator interplay in pregnant women with convalescent COVID-19: an exploratory study

IntroductionSARS-CoV-2 infection during pregnancy can induce changes in the maternal immune response, with effects on pregnancy outcome and offspring. This is a cross-sectional observational study designed to characterize the immunological status of pregnant women with convalescent COVID-19 at distinct pregnancy trimesters. The study focused on providing a clear snapshot of the interplay among serum soluble mediators.MethodsA sample of 141 pregnant women from all prenatal periods (1st, 2nd and 3rd trimesters) comprised patients with convalescent SARS-CoV-2 infection at 3-20 weeks after symptoms onset (COVID, n=89) and a control group of pre-pandemic non-infected pregnant women (HC, n=52). Chemokine, pro-inflammatory/regulatory cytokine and growth factor levels were quantified by a high-throughput microbeads array.ResultsIn the HC group, most serum soluble mediators progressively decreased towards the 2nd and 3rd trimesters of pregnancy, while higher chemokine, cytokine and growth factor levels were observed in the COVID patient group. Serum soluble mediator signatures and heatmap analysis pointed out that the major increase observed in the COVID group related to pro-inflammatory cytokines (IL-6, TNF-α, IL-12, IFN-γ and IL-17). A larger set of biomarkers displayed an increased COVID/HC ratio towards the 2nd (3x increase) and the 3rd (3x to 15x increase) trimesters. Integrative network analysis demonstrated that HC pregnancy evolves with decreasing connectivity between pairs of serum soluble mediators towards the 3rd trimester. Although the COVID group exhibited a similar profile, the number of connections was remarkably lower throughout the pregnancy. Meanwhile, IL-1Ra, IL-10 and GM-CSF presented a preserved number of correlations (≥5 strong correlations in HC and COVID), IL-17, FGF-basic and VEGF lost connectivity throughout the pregnancy. IL-6 and CXCL8 were included in a set of acquired attributes, named COVID-selective (≥5 strong correlations in COVID and <5 in HC) observed at the 3rd pregnancy trimester.Discussion and conclusionFrom an overall perspective, a pronounced increase in serum levels of soluble mediators with decreased network interplay between them demonstrated an imbalanced immune response in convalescent COVID-19 infection during pregnancy that may contribute to the management of, or indeed recovery from, late complications in the post-symptomatic phase of the SARS-CoV-2 infection in pregnant women

Avaliação do desempenho de parâmetros imunológicos como indicadores de progressão clínica da infecção crônica pelo HTLV-1

Neste estudo, foi avaliado o desempenho isolado e combinado de parâmetros laboratoriais, percentual de linfócitos B (%LB), a razão entre células T/B e o %CD8+HLA-DR+/CD8+, na identificação de indivíduos assintomáticos-AS ou portadores de HAM/TSP-HT numa população de casos soropositivos para HTLV-1. Índices expressos em porcentagem demonstram que cada parâmetro, isoladamente, apresenta desempenho moderado, com co-negatividade=83% e 91% para %LB e razão entre células T/B, respectivamente e co-positividade=78% para %CD8+HLA-DR+/CD8+. A análise combinada (%CD8+HLA-DR+/CD8+ e razão T/B) não revelou ganho significativo no desempenho (co-positividade=75%, co-negatividade=74%). A análise das razões de verossimilhança em diferentes faixas de valores, para os parâmetros isolados, revelou que um indivíduo soropositivo para HTLV-1 com %LB<7%, razão entre células T/B>11 e %CD8+HLA-DR+/CD8+>70% possui, respectivamente, 11, 19 e quase 10 vezes mais chances de pertencer ao grupo HT. Portanto, recomenda-se o uso desses indicadores fenótipos na propedêutica laboratorial complementar de monitoração da progressão clínica da infecção crônica pelo HTLV-1

Protease inhibitors from Theobroma cacao impair SARS-CoV-2 replication in vitro

SARS-CoV-2 is a newly emerging virus from the Coronaviridae family that has already infected over 700 million people worldwide and killed over 6 million. This virus uses protease molecules to replicate and infect the host, which makes these molecules targets for therapeutic substances to eliminate the virus and treat infected people. Through the protein-protein molecular docking approach, we detected two cystatins from Theobroma cacao, TcCYS3 and TcCYS4, described as papain-like protease inhibitors. These inhibitors decreased SARS-CoV-2 genomic copies without toxicity to Vero cells. There is a need to perform comprehensive studies in relevant animal models and to investigate the action mechanisms of protease inhibitors from Theobroma cacao that control the replication of SARS-CoV-2 in human cells

Evaluation of the performance of immunological parameters as indicators for clinical progression of chronic HTLV-1 infection

Submitted by Nuzia Santos ([email protected]) on 2013-06-19T13:59:05Z No. of bitstreams: 1 32.COELHO-DOS-REIS.pdf: 591379 bytes, checksum: 9fd6e6080f079fe499400675652dad9f (MD5)Made available in DSpace on 2013-06-19T13:59:05Z (GMT). No. of bitstreams: 1 32.COELHO-DOS-REIS.pdf: 591379 bytes, checksum: 9fd6e6080f079fe499400675652dad9f (MD5) Previous issue date: 2007PIBIC/CNPq, CPqRR/FIOCRUZ e Fundação HEMOMINASFundação Oswaldo. Centro de Pesquisas René Rachou. Cruz. Belo Horizonte, MG, Brasil/ Universidade Federal de Minas Gerais Instituto de Ciências Biológicas. Departamento de Microbiologia. Belo Horizonte, MG, BrasilFundação Oswaldo. Centro de Pesquisas René Rachou. Cruz. Belo Horizonte, MG, BrasilUniversidade Federal dos Vales do Jequitinhonha e Mucuri. Diamantina, MG, Brasil.Hospital Sarah Kubitschek, Belo Horizonte, MG, BrasilFundação Centro de Hematologia e Hemoterapia de Minas Gerais. Belo Horizonte, MG, BrasilFundação Centro de Hematologia e Hemoterapia de Minas Gerais. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais Instituto de Ciências Biológicas. Departamento de Microbiologia. Belo Horizonte, MG, BrasilFundação Oswaldo. Centro de Pesquisas René Rachou. Cruz. Belo Horizonte, MG, BrasilNeste estudo, foi avaliado o desempenho isolado e combinado de parâmetros laboratoriais, percentual de linfócitos B (%LB), a razão entre células T/B e o %CD8 + HLA-DR + /CD8 + , na identificação de indivíduos assintomáticos-AS ou portadores de HAM/TSP-HT numa população de casos soropositivos para HTLV-1. Índices expressos em porcentagem demonstram que cada parâmetro, isoladamente, apresenta desempenho moderado, com co-negatividade=83% e 91% para %LB e razão entre células T/B, respectivamente e co-positividade=78% para %CD8 + HLA-DR + /CD8 + . A análise combinada (%CD8 + HLA-DR + /CD8 + e razão T/B) não revelou ganho significativo no desempenho (co-positividade=75%, co-negatividade=74%). A análise das razões de verossimilhança em diferentes faixas de valores, para os parâmetros isolados, revelou que um indivíduo soropositivo para HTLV-1 com %LB11 e %CD8 + HLA-DR + /CD8 +>70% possui, respectivamente, 11, 19 e quase 10 vezes mais chances de pertencer ao grupo HT. Portanto, recomenda-se o uso desses indicadores fenótipos na propedêutica laboratorial complementar de monitoração da progressão clínica da infecção crônica pelo HTLV-1.This study evaluated the performance of single and combined laboratory parameters, B-lymphocyte percentages (%LB), T/B cell ratio and %CD8 + HLA-DR + /CD8 + , to differentiate asymptomatic cases (AS) from HAM/TSP patients (HT) within a population of HTLV-1 seropositive cases. Percentage indices demonstrated that each parameter alone presented moderate performance, with co-negativity of 83 and 91% for %LB and T/B cell ratio, respectively, and co-positivity of 78% for %CD8 + HLA-DR + /CD8 + . Combined analysis (%CD8 + HLA-DR + /CD8 + and T/B cell ratio) did not show any substantial performance enhancement (co-positivity = 75% and co-negativity = 74%). Likelihood ratio analysis using different value ranges for the separate parameters revealed that HTLV-1 seropositive cases with %LB11 and %CD8+HLA-DR+/CD8+>70% would have, respectively, 11, 19 and 10 times greater chance of belonging to the HT group. Therefore, use of these phenotypic indicators as complementary laboratory methods for monitoring the clinical progression of chronic HTLV-1 infection is recommended

In-house ELISA method to analyze anti-Trypanosoma cruzi IgG reactivity for differential diagnosis and evaluation of Chagas disease morbidity.

Submitted by Nuzia Santos ([email protected]) on 2012-03-08T19:15:10Z No. of bitstreams: 1 Santos, Lilian da Silva et al. Metodo de ELISA in-house na analise da reatividade de IgG anti-Trypanosoma cruzi para o diagnostico diferencial e avaliacao da morbidade da doenca de Chagas..pdf: 1806322 bytes, checksum: 0dd3b1fe9f3a32d5ece838221871989e (MD5)Made available in DSpace on 2012-03-08T19:15:10Z (GMT). No. of bitstreams: 1 Santos, Lilian da Silva et al. Metodo de ELISA in-house na analise da reatividade de IgG anti-Trypanosoma cruzi para o diagnostico diferencial e avaliacao da morbidade da doenca de Chagas..pdf: 1806322 bytes, checksum: 0dd3b1fe9f3a32d5ece838221871989e (MD5) Previous issue date: 2012Universidade Federal de Ouro Preto. Nucleo de Pesquisas em Ciencias Biologicas. Ouro Preto, MG, Brasil.Universidade Federal de Minas Gerais, Belo Horizonte. Departamento de Clinica Medica. Belo Horizonte, MG, BrasilUniversidade Federal de Ouro Preto. Nucleo de Pesquisas em Ciencias Biologicas. Ouro Preto, MG, BrasilUniversidade Federal de Ouro Preto. Nucleo de Pesquisas em Ciencias Biologicas. Ouro Preto, MG, Brasil/Universidade Federal de Ouro Preto. Departamento de Ciencias Biologicas. Ouro Preto, MG, BrasilUniversidade Federal de Ouro Preto. Nucleo de Pesquisas em Ciencias Biologicas, Ouro Preto, MG/Universidade Federal do Vale do Jequitinhonha e Mucuri. Departamento de Farmacia. Diamantina, MG, BrasilFundacao Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Laboratorio de Biomarcadores de Diagnostico e Monitoracao. Belo Horizonte, MG, Brasil.Drexel University College of Medicine. Department of Microbiology & Immunology. Doylestown, PA, USA.Fundacao Oswaldo Cruz. Laboratorio de Doencas Parasitarias. Rio de Janeiro, RJ, Brasil.Fundacao Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Laboratorio de Biomarcadores de Diagnostico e Monitoracao. Belo Horizonte, MG, Brasil.Universidade Federal de Ouro Preto. Nucleo de Pesquisas em Ciencias Biologicas, Ouro Preto, MG/Universidade Federal de Ouro Preto. Departamento de Analises Clinicas. Ouro Preto, MG, Brasil.Introdução: O objetivo foi desenvolver um metodo sorologico in-house de alta especificidade e sensibilidade para diagnosticar e monitorar a morbidade da doenca de Chagas. Métodos: Para tal, a reatividade sorologica de IgG e subclasses foi testada em soros de pacientes chagásicos de Berilo, Vale do Jequitinhonha/MG/Brasil. A reatividade sorologica foi tambem avaliada em amostras de pacientes com outras doencas infecto-contagiosas relevantes, incluindo o HIV, virus da hepatite C (VHC), sifilis (SYP), leishmaniose visceral (LV), leishmaniose tegumentar americana (LTA) e controles nao infectados (NI) para verificar o desempenho do metodo. Outras analises foram feitas para avaliar a aplicabilidade desta metodologia no monitoramento da morbidade da doenca de Chagas. Com este proposito os pacientes com doenca de Chagas foram anteriormente classificados em tres grupos: indeterminados (IND), cardiacos (CARD) e digestivos/mistos (DIG/Mis) conforme seu estado clinico. Resultados: A analise da reatividade sorologica de IgG total na diluicao 1:40 mostrou ser uma abordagem importante no diagnostico da doenca de Chagas (100% de sensibilidade e especificidade e ausencia de reacao cruzada com as demais infeccoes). A analise das subclasses de IgG mostrou reacaocruzada principalmente com NI, LV e LTA em todas as diluicoes. O grupo IND apresentou a maior reatividade para IgG3 e o grupo DIG/Mis apresentou nivel mais elevado de IgG se comparados aos grupos IND e CARD. Conclusões: Estes achados demonstram que o método de ELISA in-house apresenta uma promissora aplicabilidade no diagnostico diferencial e na avaliacao da morbidade da doenca de Chagas.The goal was to develop an in-house serological method with high specificity and sensitivity for diagnosis and monitoring of Chagas disease morbidity. Methods: With this purpose, the reactivities of anti-T. cruzi IgG and subclasses were tested in successive serum dilutions of patients from Berilo municipality, Jequitinhonha Valley, Minas Gerais, Brazil. The performance of the in-house ELISA was also evaluated in samples from other relevant infectious diseases, including HIV, hepatitis C (HCV), syphilis (SYP), visceral leishmaniasis (VL), and American tegumentary leishmaniasis (ATL), and noninfected controls (NI). Further analysis was performed to evaluate the applicability of this in-house methodology for monitoring Chagas disease morbidity into three groups of patients: indeterminate (IND), cardiac (CARD), and digestive/mixed (DIG/Mix), based on their clinical status. Results: The analysis of total IgG reactivity at serum dilution 1:40 was an excellent approach to Chagas disease diagnosis (100% sensitivity and specificity). The analysis of IgG subclasses showed cross-reactivity, mainly with NI, VL, and ATL, at all selected serum dilutions. Based on the data analysis, the IND group displayed higher IgG3 levels and the DIG/Mix group presented higher levels of total IgG as compared with the IND and CARD groups. Conclusions: These findings demonstrated that methodology presents promising applicability in the analysis of anti-T. cruzi IgG reactivity for the differential diagnosis and evaluation of Chagas disease morbidity